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Abstract
Abstract The mechanism of the uterotrophic and antiuterotrophic action of testosterone in the rat is unknown. Since testosterone does not compete with estradiol-17β for receptor sites, the possible direct interaction of testosterone with uterine components in the rat was investigated. Following the administration of [3H]testosterone to immature female rats, the hormone is selectively taken up by uterine nuclei and is retained for 15 to 30 min. Thereafter, the hormone is gradually released and is virtually eliminated from the uterine nuclei over a period of 2 hours. Very low levels of radioactivity are accumulated in nuclei of diaphragm and other tissues. The simultaneous administration of non-labeled testosterone reduces the nuclear uptake of [3H]testosterone in the uterus by about 80% while it has no effect on the uptake of the labeled hormone by diaphragm nuclei. In the cytosol as well as the nuclear extract of the uterus, [3H]testosterone is bound to macromolecules which are excluded from Sephadex G-50. The nuclear [3H]testosterone macromolecule complex is also excluded from Sephadex G-200. No association of [3H]testosterone to macromolecules in cytosol or nuclei of diaphragm was observed. Uptake and binding of [3H]testosterone to nuclear components were also demonstrated in vitro following incubation of uteri at 37° in Eagle's Hela culture medium. Binding to nuclear components is highly specific for testosterone and the nuclear binding sites are saturated with low concentrations of the hormone. 5α-Dihydrotestosterone is much less effective than testosterone in competing with [3H]testosterone for the nuclear binding sites. Estradiol-17β reduces the nuclear accumulation of [3H]testosterone by only 20 to 30% while progesterone, cortisol, and cyproterone acetate at the concentrations used have no effect. Studies using cell-free systems indicate that binding of testosterone to cytoplasmic components is a prerequisite step for the transfer of the hormone to the nucleus. In vitro and in vivo studies show that the immature rat uterus lacks the capacity to convert testosterone to 5α-dihydrotestosterone or estrogens, to any significant extent. These results demonstrate that the immature rat uterus contains cytoplasmic and nuclear binding components (receptors) with high affinity and specificity for testosterone. Thus the uterotrophic and antiuterotrophic action of testosterone appears to be a direct action of the hormone by a mechanism distinct from that of estradiol-17β. The data also demonstrate that the uterine androgen-binding components are different from those found in the rat prostate with regard to their relative affinity for testosterone and 5α-dihydrotestosterone. Therefore the intracellular active form of androgen may vary from tissue to tissue. Whereas 5α-dihydrotestosterone appears to be the major active androgen in the rat prostate, in other tissues such as the uterus the predominant active androgen may be testosterone itself.
Highlights
Larger amounts of nonlabeled testosterone did not reduce the uptake of labeled hormone in the uterus to more than 507, 1 hour after the injection, and less inhibition was observed at earlier times
Whereas Sardihydrotestosterone appearsto be the major active androgen in the rat prostate, in other tissues such as the uterus the predominant active androgen may be testosterone itself
Summary
In Vivo Uptake of [aH] Testosterone by Rat Tissues-Immature female hooded rats, 20 to 22 days old, were used in these studies.[3H]Testosterone, 0.1 fig in 0.5 ml of 0.9% NaCl solution containing 0.5% ethanol, was injected intraperitoneally and the animals were killed by decapitation at different time intervals after the injection. In Vivo Uptake of [aH] Testosterone by Rat Tissues-Immature female hooded rats, 20 to 22 days old, were used in these studies. Aliquots of the tissues (20 to 100 mg) or serum (0.2 ml) were placed in scintillation vials containing 5 ml of methylene chloride, the vials were sealed tightly to prevent evaporation of the solvent and incubated overnight at 25” with shaking. In Vitro Incubation of Rat Tissues-Whole uteri or slices of diaphragm from untreated rats were incubated with an appropriate concentration of [3H]testosterone in Eagle’s HeLa culture medium [6] under an atmosphere of 95% 02-5% COz in a shaking water bath at 37”. Competition studies were performed by incubating the tissues with [3H]testosterone and a lo-fold excess of nonlabeled steroid
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